This is a 371 of International Application PCT/GB00/02500, filed Jun. 29, 2000, which claims priority from GB 9915589.7 filed Jul. 2, 1999.
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
Prior art document U.S. Pat. No. 4,022,900 (Marion Laboratories Inc.) discloses benzamido-1, 2, 3,4-tetrahydroisoquinolines having anti-hypertensive properties. Prior art documents International Application Publication Numbers WO 97/48683, WO98/41507, WO 98/41508, WO 97/48683, WO 99/21836 and WO 99/31068 (SmithKline Beecham) disclose isoquinolinyl benzamide derivatives and their use as anticonvulsants.
It has now been surprisingly found that carboxamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaernia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Accordingly, in a first aspect, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof: 
wherein:
Q is a monocyclic or bicyclic aryl or heteroaryl ring;
R1 is hydrogen:
R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3SO2xe2x80x94, CF3COxe2x80x94, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylSxe2x80x94, C1-6alkylSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94, (C1-4alkyl)NHSO2xe2x80x94, (C1-4alkyl)2NCOxe2x80x94, (C1-4alkyl)NHCOxe2x80x94, or CONH2, or xe2x80x94NR3R4 where R3 is hydrogen or C1-4 alkyl, and R4 is hydrogen, C1-4alkyl, formyl, xe2x80x94CO2C1-4alkyl, or xe2x80x94COC1-4alkyl, or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by xe2x80x94OH or =O:
X is halogen, C1-6 alkoxy, C1-6 alkyl, or C1-6 perfluoroalkyl, and;
Y is hydrogen, halogen, C1-6 alkoxy, C1-6 alkyl, or C1-6 perfluoroalkyl;
with the proviso that the following compounds are excluded:
N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl )-4-azidobenzamide, and;
N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide.
The compounds of this invention are typically (tetrahydroisoquinolin-7-yl) carboxamides.
The ring system Q is typically unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl. When two R2 groups form a carbocyclic ring, this is typically a 5-7-membered ring, and Q may be a naphthalene, indane, or indanone ring system.
Alkyl groups of formula (I), including alkyl groups that are part of other moieties such as alkoxy or acyl, may be straight or branched chain. Phenyl groups in R2, including phenyl groups that are part of other moieties, may be substituted independently with one or more groups selected from halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylcarbonyl. Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.
A suitable group of compounds of this invention consists of compounds of formula (IA): 
another suitable group of compounds consists of compounds of formula (IB): 
wherein R1, R2, X, and Y are as hereinbefore defined.
A suitable group of compounds of formula (I) are those wherein;
R1 is hydrogen;
R2 is hydrogen or one or more of the following groups: methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro,iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl, or two R2 groups form a benzene, cyclopentane or cyclopentanone ring;
X is chloro, bromo, iodo, fluoro C1-6 perfluoroalkyl, and;
Y is hydrogen, halogen, C1-6 alkoxy, C1-6 alkyl, or, C1-6 perfluoroalkyl.
A preferred group of compounds of formula (I) are those wherein;
R1 is hydrogen;
R2 is hydrogen or one or more of the following groups;
methyl, ethyl, iso-propyl, n-butyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, phenoxy, acetoxy, nitro, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, trifluoromethyl, pentafluoroethyl, azido, trifluoromethoxy;
X is iodo, chloro, bromo or trifluoromethyl, and;
Y is hydrogen , chloro, bromo, iodo or trifluoromethyl.
The following compounds are examples of compounds of formula (I), but do not limit the invention in any way:
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethyl benzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl )-4-methoxy-3-trifluoromethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propoxybenzaniide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl )-4-iso-propoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide
N-(5-Trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
N-(5-Trifluoromethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(5-Trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propoxybenzamide.
When synthesised these compounds are often in salt form such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates such as hydrates, and these also form part of this invention.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit dose composition, such as an oral unit dose including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Accordingly, the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression , panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression , panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaernia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis. migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaernia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
In a further aspect, the present invention provides a process for the preparation of compounds of formula (I) as hereinbefore defined which process comprises reacting a compound of formula (II); 
wherein R1A is R1 or preferably a group convertible to R1, and R1, X, and Y are as hereinbefore defined, with a compound of formula (III) 
wherein
Q is as hereinbefore defined;
Y is a leaving group such as Cl or OH, and;
R2A represents hydrogen or up to three substituents as hereinbefore defined for R2 wherein the R2A groups may independently be R2 groups or groups convertible to R2;
and where required converting an R1A or R2A group to a R1 or R2 group respectively;
converting one R1 or R2 group to another R1 or R2 group;
converting a salt product to the free base or a pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
Reaction of a compound of formula (III) which is an acid chloride (Yxe2x95x90Cl) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the compound of formula (III) is an aromatic acid (Yxe2x95x90OH), conventional conditions for condensation of such acids with amines may be used, for example reacting the components in a mixture of (dimethylaminopropyl)-ethyl-carbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formamide.
Conversions of an R1A or R2A group-to a R1 or R2 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one R1 or R2 group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
The compound of formula (II), wherein R1A is hydrogen or trifluoroacetyl and X and Y are both chloro may be prepared from the compound of formula (II) wherein R1A is hydrogen or trifluoroacetyl, X is chloro, and Y is hydrogen by reaction with N-chloromorpholine in glacial acetic acid.
The compound of formula (II) wherein R1A is hydrogen or trifluoroacetyl, X is chloro, and Y is hydrogen may be prepared from the compound of formula (IV) wherein R1A is hydrogen or trifluoroacetyl, X is chloro and Y is hydrogen by reduction with tin (II) chloride in concentrated hydrochloric acid. 
The compound of formula (IV) wherein R1A is hydrogen or trifluoroacetyl, X is chloro and Y is hydrogen may be prepared from the compound of formula (IV) wherein X is iodo and Y is hydrogen by heating in the presence of copper (I) chloride in an inert atmosphere.
The compound of formula (IV) wherein R1A is hydrogen or trifluoroacetyl, X is iodo and Y is hydrogen may be prepared from the compound of formula (V) wherein R1A is hydrogen or trifluoroacetyl and Y is hydrogen by reaction with N-iodosuccinimide in triflic acid according to the procedure of G. A. Olah et al., J.Org. Chem., 1993, 58, 3194. 
The compound of formula (V) wherein R1A is hydrogen and Y is hydrogen may be prepared from the compound of formula (VI) wherein Y is hydrogen by hydrolysis with potassium carbonate in methanol. 
The compound of formula (VI) wherein Y is hydrogen may be prepared by reaction of N-(nitrophenyl)ethyl trifluoroacetamide and paraformaldehyde in acidic conditions using the procedure of Stokker, Tet.Lett.,1996, 37, 5453. N-(nitrophenyl)ethyl trifluoroacetamides can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below.
Compounds of formula (II) may also be prepared from the corresponding aminoisoquinoline (or its nitro-analogue) of formula (VII) 
where RN is NH2 or NO2 and X and Y are as hereinbefore defined by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially lodo, or tosylate and R1A is benzyl or 4-methoxybenzyl to obtain an intermediate of formula (VIII). 
which can be reduced, for example using sodium borohydride, or hydrogenated, for example using hydrogen and a palladium/activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II). When the compound of formula (VIII) is replaced by a nitroisoquinoline, the nitro group is converted to an amino group in the hydrogenation step.
When the intended R1 is hydrogen, the nitrogen atom of the tetrahydroisoquinoline or isoquinoline molecule is preferably protected conventionally, prior to the coupling step that forms the carboxamide of formula (I), for example by tert.-butoxycarbonyl, trifluoroacetyl or benzyl. The compound can be deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride or potassium carbonate in aqueous methanol, catalytic hydrogenolysis.
Amino/nitro-isoquinolines of formula (VIII) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature.
The substituents X and Y may be introduced during any of the procedures above, for example by conventional substitution of the aromatic ring of compounds of formula (IV), (V) or (VIII) or may be present on commercially available starting materials usable in the above described procedures. Most suitably the substituents X and Y are introduced to a compound of formula (IX) 
where RN and R1A are as hereinbefore defined. For example X as halogen may be incorporated by reaction with a halosuccinimide, or Xxe2x95x90CF3 may be introduced by displacement of iodo with copper(I)trifluoroacetate as illustrated in the descriptions below.
Compounds of formula (III) may be prepared by further substitution of commercially available benzoic acid or thiophene carboxylic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correspondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid. Examples of these procedures are documented in WO 98/41507 and WO98/41508.
Where the above described intermediates are novel compounds, they also form part of this invention.
The preparation of compounds of this invention is further illustrated by the following Descriptions and Examples, which do not limit the invention in any way:
Description 1
A solution of trifluoroacetic anhydride (10.6 ml) in dichloromethane (100 ml) was added dropwise to a stirred solution of 2,6-lutidine (17.44 ml) and 4-nitrophenethylamine hydrochloride (15.2 g; 75 mmol) at 0xc2x0 C. The mixture was stirred at 25xc2x0 C. overnight under argon and then washed with dilute citric acid (xc3x972), brine and dried over Na2SO4. The material in the organic phase gave the title compound D1 as a pale yellow solid (19.04 g).
Description 2
The product from Description 1 (2.26 g; 9.15 mmol) and paraformaldehyde (0.45 g; 14.4 mmol) in acetic acid (10 ml) and conc. H2SO4 (15 ml) were stirred at 25xc2x0 C. for 20 h according to the procedure of G. E. Stokker., Tet. Lett., 1996, 37, 5453. Work up afforded the title compound D2 as a white solid (2.17 g).
1H NMR (CDCl3) xcex4: 3.10 (2H, m), 3.92 (2H, m), 4.85+4.92 (2H, 2xs), 7.38 (1H, t), 8.10 (2H, m); m/z (EI): 274 (M+)
Description 3
The product from Description 2 (17.22 g; 63 mmol) was hydrolysed at room temperature using a solution of potassium carbonate (46.6 g) in 10% aqueous methanol (660 ml). Work-up with dichloromethane gave the title compound (11 g).
Description 4
The product from Description 3 (750 mg; 3.9 mmol) and N-iodosuccinimide (1.13 g) in triflic acid (5 ml) was stirred at 25xc2x0 C. overnight according to the procedure of G. A. Olah et al., J.Org. Chem., 1993, 58, 3194. The mixture was poured cautiously into saturated NaHCO3 and then extracted into ether (2xc3x97). The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporation in vacuo gave a residue. Chromatography on Kieselgel 60 in 2% methanol-dichloromethane gave the title compound (650 mg).
Description 5
A solution of the product from Description 4 (650 mg, 2.14 mmol) in ethanol (20 ml) at 50xc2x0 C. was treated with a solution of tin (II) chloride (1.42 g) in c. HCl (3 ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 (5% methanol-dichloromethane) gave the title compound (428 mg; 73%).
Description 6
The title compound was prepared from the product from Description 2 using a procedure similar to that of Description 4.
m/z (API+): 401 (MH+; 45%).
Description 7
The product from Description 6 (810 mg) in dry DMF (15 ml) was treated with copper (I) chloride (605 mg) and heated at 125xc2x0 C. under argon for 18 h. After cooling, the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was then washed with water (xc3x973), aqueous sodium thiosulfate, brine and dried (MgSO4). Evaporation in vacuo gave the title compound as a red gum (519 mg).
1H NMR (CDCl3) xcex4: 3.09 (2H, m), 3.96 (2H, m), 4.85, 4.92 (2H, 2s, rotamers), 7.99 (1H, m), 8.20 (1H, m).
Description 8
A solution of the product from Description 7 (2.14 mmol) in ethanol (20 ml) at 50xc2x0 C. was treated with a solution of tin (II) chloride (1.42 g) in c. HCl (3 ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 (5% methanol-dichloromethane) gave the title compound.
1H NMR (CDCl3) xcex4: 2.84 (2H, m), 3.67 (2H, brs), 3.83 (2H, m), 4.61, 4.67 (2H, 2s, rotamers), 6.33 (1H, m), 6.65 (1H, m).
Description 9
Chlorination of the product from Description 8 (150 mg; 0.54 mmol) with N-chloromorpholine (100 mg; 0.89 mmol) in glacial acetic acid (6 ml) for 30 min at 25xc2x0 C. followed by basic work-up similar to that of Description 8 gave the title compound (70 mg).
m/z (API+): 315, 313 (MH+; 50% expected isotope pattern)
Description 10
The title compound was prepared from the product from Description 6 and copper (II) bromide using a method similar to that of Description 7 followed by tin (II) chloride reduction according to the procedure used in Description 8.
1H NMR (CDCl3) xcex4: 2.86 (2H, m), 3.68 (2H, brs), 3.85 (2H, m), 4.62, 4.69 (2H, 2s, rotamers), 6.39 (1H, m), 6.85 (1H, m).
Description 11
The title compound was prepared from the product from Description 6 and potassium trifluoroacetate using a method similar to that of Preparation 6 followed by hydrogenation over 10% palladium on carbon (100 mg) in ethanol at atmospheric pressure overnight. The catalyst was removed by filtration through a pad of Kieselguhr and evaporation in vacuo gave the title compound.
1H NMR (CDCl3) xcex4: 2.98 (2H, brm), 3.82 (4H, m), 4.67, 4.72 (2H, 2s, rotamers), 6.60 (1H, m), 6.88 (1H, m).
Preparation 1
A mixture of 3-tert-butylphenol (25.25 g, 0.1680 mole), acetic anhydride (34.31 g, 0.336 mole) and sodium acetate (13.78 g, 0.1680 mole) was heated at 100xc2x0 C. for 2 h. On cooling the mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the acetate compound as an oil (33.33 g).
Preparation 2
A mixture of the acetate of Preparation 1 (33.23 g, 0.173 mole) and AlCl3 (25.61 g. 0.192 mole) was placed in an oil bath preheated to 120xc2x0 C. and stirred mechanically. Then the oil bath temperature was raised to 165xc2x0 C. and maintained for 45 min before being allowed to cool to 120xc2x0 C. Then water was added dropwise into the reaction mixture (4xc3x97250 ml) to steam distil the product (bath temp 190-200xc2x0 C.). The distillate was extracted with ether and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford 4-tert-butyl-2-hydroxy acetophenone as an oil (18.05 g).
Preparation 3
A suspension of 4-tert-butyl-2-hydroxy acetophenone (12.65 g), potassium carbonate (13.14 g) and dimethyl sulfate (8.99 ml) in acetone (200 ml) was refluxed for 48 h. After cooling, the mixture was filtered. The solvent was then removed in vacuo and the residue taken up in dichloromethane and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a yellow oil (12.05 g).
Preparation 4
The acetophenone of Preparation 3 (11.0 g, 53 mmol) was added to a solution of sodium hydroxide (28.68 g), sodium hypochlorite (182 ml, 12% w/w) and water (70 ml) at 80xc2x0 C. with stirring. After heating for 1.25 h, the mixture was cooled to 0xc2x0 C. and a solution of sodium metabisulphite (41.1 g) in water (170 ml) was added. The mixture was stirred for 15 min and then acidified (pH1) with conc. HCl (45 ml). Work-up with ethyl acetate gave the title compound as a white solid (8.9 g).
1H NMR (DMSO-d6) xcex4: 1.30 (9H, s), 3.85 (3H, s), 6.96-7.12 (2H, m), 7.60 (1H, d), 12.30-12.60 (1H, br).
Preparation 5
To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) in chloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87 g).
Preparation 6
5-Bromo-2,4-dimethoxybenzoic acid methyl ester (1.5 g; 5.4 mmol) in DMF (25 ml) and toluene (8 ml) under argon was treated with potassium trifluoroacetate (1.53 g; 10.1 mmol) and copper (I) iodide (2.1 g, 10.9 mmol). The mixture was heated to 170xc2x0 C. with removal of water (Dean/Stark), and then at 155xc2x0 C. overnight; then allowed to cool, poured into ether and water and filtered through Kieselguhr. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave a white solid (1.03 g) which was hydrolysed in 1:1 methanolic:aqueous NaOH (50 ml) at 50xc2x0 C. Work-up gave the title compound as a white solid (1 g).
Preparation 7
The title compound was prepared from 4-ethoxybenzoic acid in a manner similar to that of Preparation 5.
1H NMR (DMSO-D6) xcex4: 1:45 (3H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 7.26 (1H, d, J=9 Hz), 7.98 (1H, dd, J=2, 9 Hz), 8.12 (1H, d, J=2 Hz)
Preparation 8
The title compound was prepared from 3-bromo4-methoxybenzoic acid and potassium trifluoroacetate in a manner similar to that of Preparation 6.
1H NMR (DMSO-D6) xcex4: 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90 (1H, d, J=2 Hz), 8.00 (1H, dd, J=2, 9 Hz), 12.70-13.10 (1H, br,exchangeable)
Preparation 9
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.
Preparation 10
The title compound was prepared from 4-ethylbenzoic acid.
1H NMR (DMSO-D6) xcex4: 1.20 (3H, t,J=7 Hz), 2.78 (2H, q, J=7 Hz), 7.50 (1H, d, J=8 Hz), 7.90 (1H, dd, J=2, 8 Hz), 8.07 (1H, d, J=8 Hz
Preparation 11
Prepared as described in Preparation 6 from methyl 3-bromo4-iso-propylbenzoate and isolated as a white solid.
m/z (API): 231.1 [Mxe2x80x94H].
Preparation 12
The title compound was prepared from 4-isopropylbenzoic acid similar to that described in Procedure 1.
1H NMR (DMSO-D6) xcex4: 1.07 (6H, d, J=7 Hz), 3.13 (1H,m, overlapped), 7.48 (1H, d, J=7 Hz), 7.96 (1H, dd, J=2, 8 Hz)), 8.00 (1H, d, J=2 Hz).
Preparation 13
Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25xc2x0 C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g).
1H NMR (250 MHz, CDCl3) xcex4: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H, m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8, 2 Hz), 8.22 (1H, d, J=2 Hz)
Preparation 14
Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper(I)cyanide in N-methyl pyrrolidone (50 ml) were heated under vigorous reflux for 4 h. Work-up with ethyl acetate gave the title compound (1.0 g).
1H NMR (250 MHz, CDCl3) xcex4: 1.56 (6H, d, J=7 Hz), 4.05 (3H, s), 4.88 (1H, m), 7.13 (1H, d, J=8 Hz), 8.31 (1H, dd, J=8, 2 Hz), 838 (1H, d, J=2 Hz)
Preparation 15
Saponification of P14 gave the acid as an off white solid.
1H NMR (250 MHz, CDCl3) xcex4: 1.35 (6H, d, J=7 Hz), 4.67 (1H, m), 6.90 (1H, d, J=8 Hz), 8.11 (1H, dd, J=8, 2 Hz), 8.19 (1H, d, J=2 Hz)
Preparation 16
The bromo ester (2.5 g, 8.3 mmol) in dry dioxan (30 ml) was treated with (1-ethoxyvinyl)-tributyl tin (3.58 g, 9.9 mmol) followed by tetrakis triphenylphosphine palladium(o) (0.48 g, 0.4 mmol) and heated at 100xc2x0 for 18 h. After cooling, the mixture was acidified and aqueous work-up and extraction into ethyl acetate gave a coloured oil (5.6 g). Flash chromatography on Kieselgel 60 [hexane to 20% EtAc/hexane gave the title compound as a yellow oil (2.3 g).
m/z (API+): 265.2 (MH+, 90%).
Preparation 17
Saponification of the ester P16 (2.3 g) gave the title compound as a white solid (1.3 g).
1H NMR (250 MHz, CDCl3) xcex4: 1.48 (6H, d, J=7 Hz), 2.63 (3H, s), 4.80 (1H, m), 7.00 (1H, d, J=8 Hz), 8.17 (1H, dd, J=8, 2 Hz), 8.46 (1H, d, J=2 Hz)
Preparation 18
1H NMR (250 MHz, CDCl3) xcex4: 1.53 (3H, d, J=7 Hz), 3.91 (3H, s), 4.25 (2H, q, J=7 Hz), 7.02 (1H, d, J=8 Hz), 8.25 (1H, dd, J=8,2Hz), 8.32 (1H, d, J=2 Hz).
Preparation 19
Prepared in a similar manner to that described for Preparations 16 and 17.
1H NMR (250 MHz, CDCl3) xcex4: 1.53 (3H, t, J=7 Hz), 2.65 (3H, s), 4.23 (2H, q, J=7 Hz), 7.01 (1H, d, J=8 Hz), 8.19 (1H, dd, J=8, 2 Hz), 8.48 (1H, d, J=2 Hz).
Preparation 20
1H NMR (DMSO-D6) xcex4: 1.39 (3H, t, J=7 Hz), 4.20 (2H, q, J=7 Hz), 7.22 (1H, d, J=7 Hz), 7.87 (2H, m).
Procedure 1a
Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) in N-methyl-2-pyrrolidinone (30 ml). The mixture was stirred under argon and boiled under reflux for 4 h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg).
1H NMR (250 MHz, CDCl3) xcex4: 1.33 (6H, d, J=7 Hz), 3.38 (1H, sep, J=7Hz), 3.89 (3H, s), 3.98 (3H, s), 6.91 (1H, s), 8.08 (1H, s); m/z (API+): 234 (MH+, 30%).
Procedure 1b
2N NaOH (1.25 ml) was added to a solution of the methyl ester P1a (490 mg) in methanol (10 ml). The solution was stirred overnight at room temperature. The solution was then diluted with water, concentrated in vacuo and washed with ethyl acetate. The aqueous phase was then acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to dryness giving the product as a white solid (418 mg).
1H NMR (250 MHz, CDCl3) xcex4: 1.35 (6H, d, J=7 Hz), 3.43 (1H, sep, J=7 Hz), 4.14 (3H,s), 7.00 (1H, s), 8.41 (1H, s); m/z (API+): 220 (MH+, 100%).
Procedure 2
5-Chloro-2-thenoic acid (90 mg, 0.55 mmol) and oxalvl chloride (0.05 ml, 0.6 mmol) in dichloromethane (2 ml) was treated with 2 drops of DMF and stirred at at 25xc2x0 C. for 30 min. Evaporation in vacuo gave a solid which was added to a solution of D8 (155 mg, 0.55 mmol) in dichloromethane (10 ml) containing triethylamine (0.1 ml). After 20 h at room temperature, the mixture was diluted with ethyl acetate (100 ml) and washed with 1N HCl (100 ml), water (100 ml), brine (50 ml) and dried (MgSO4). Evaporation in vacuo gave the title compound as a white solid (148 mg).
1H NMR (CDCl3) xcex4: 2.96 (2H, m), 3.88 (2H, m), 4.73, 4.77 (2H, 2s, rotamers), 6.95 (1H, d, J=5 Hz), 7.20-7.60 (3H, m), 7.70 (1H, br); m/z (API+) 424.8, 422.9 (MH+; 100%).